Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

被引：114

作者：

Broce, Iris ^{[1
]}

Karch, Celeste M. ^{[2
]}

Wen, Natalie ^{[2
]}

Fan, Chun C. ^{[3
]}

Wang, Yunpeng ^{[4
,5
]}

Tan, Chin Hong ^{[1
]}

Kouri, Naomi ^{[6
]}

Ross, Owen A. ^{[6
]}

Hoeglinger, Guenter U. ^{[7
,8
,9
]}

Muller, Ulrich ^{[10
]}

Hardy, John ^{[11
]}

Momeni, Parastoo ^{[12
]}

Hess, Christopher P. ^{[1
]}

Dillon, William P. ^{[1
]}

Miller, Zachary A. ^{[13
]}

Bonham, Luke W. ^{[13
]}

Rabinovici, Gil D. ^{[13
]}

Rosen, Howard J. ^{[13
]}

Schellenberg, Gerard D. ^{[14
]}

Franke, Andre ^{[15
]}

Karlsen, Tom H. ^{[16
,17
,18
]}

Veldink, Jan H. ^{[19
]}

Ferrari, Raffaele ^{[11
]}

Yokoyama, Jennifer S. ^{[13
]}

Miller, Bruce L. ^{[13
]}

Andreassen, Ole A. ^{[4
,5
]}

Dale, Anders M. ^{[3
,20
,21
]}

Desikan, Rahul S. ^{[1
,13
]}

Sugrue, Leo P. ^{[1
]}

机构：

[1] Univ Calif San Francisco, Neuroradiol Sect, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[2] Washington Univ, Dept Psychiat, St Louis, MO USA

[3] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA

[4] Univ Oslo, Inst Clin Med, Norwegian Ctr Mental Disorders Res NORMENT, Oslo, Norway

[5] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[6] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[7] Tech Univ Munich, Dept Neurol, Munich, Germany

[8] German Ctr Neurodegenerat Dis DZNE, Munich, Germany

[9] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[10] Justus Liebig Univ, Inst Humangenet, Giessen, Germany

[11] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[12] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Lab Neurogenet, Lubbock, TX 79430 USA

[13] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[14] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[15] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[16] Oslo Univ Hosp, Rikshosp, Norwegian PSC Res Ctr, Res Inst Internal Med,Div Canc Med Surg & Transpl, Oslo, Norway

[17] Univ Bergen, Inst Med, Div Gastroenterol, Bergen, Norway

[18] Oslo Univ Hosp, Rikshosp, KG Jebsen Inflammat Res Ctr, Res Inst Internal Med,Div Canc Med Surg & Transpl, Oslo, Norway

[19] Univ Med Ctr Utrecht, Dept Neurol, Brain Ctr Rudolf Magnus, Utrecht, Netherlands

[20] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA

[21] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

来源：

PLOS MEDICINE | 2018年 / 15卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PROGRESSIVE SUPRANUCLEAR PALSY; AMYOTROPHIC-LATERAL-SCLEROSIS; LOBAR DEGENERATION; COMMON VARIANTS; CORTICOBASAL DEGENERATION; PARKINSONS-DISEASE; RISK VARIANTS; IDENTIFIES; LOCI; TAU;

D O I：

10.1371/journal.pmed.1002487

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD +/- immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

引用

页数：20

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